Project Summary/Abstract Pharmacological Chaperone Therapy for the GM2Gangliosidoses The ultimate goal of this application is the treatment of Tay-Sachs Disease (TSD) and Sandhoff Disease (SD) collectively called the GM2 Gangliosidoses with a small molecule pharmacological chaperone. Pharmacological chaperones (PCs) are small molecules that selectively bind and stabilize target proteins to facilitate proper folding, reduce premature degradation and increase the efficiency of ER export. This approach is broadly applicable to diseases where increasing the function of a specific protein (mutant or wild-type) is predicted to provide therapeutic benefit. OT1009 is a potent ?-hexosaminidase (the deficient enzyme in these diseases) targeted pharmacological chaperone with good bioavailability, blood-brain barrier penetration, high selectivity for ?-hexosaminidase and low cytotoxicity. OT1009 treatment increases levels of wild- type and mutant ?-hexosaminidase activity up to 4-fold in cells. OrPhi Therapeutics has developed the only mouse model (?R484Q/?R484Q) in which a pharmacological chaperone therapy can be tested for dosing and efficacy. We intend to use this model to test our pharmacological chaperone OT1009 in long term dosing and efficacy studies. Additionally, we intend to develop a cell based assay that discriminates between OT1009 responsive and non- responsive variants of Hex A and Hex B to determine which Tay-Sachs and Sandhoff Disease patients will be amenable to pharmacological chaperone therapy with OT1009 in future clinical trials. The GM2 Gangliosidoses are life threatening neurodegenerative diseases for which no treatment is currently available. The focus of this work is to provide pre-clinical data to support the development of OT1009 through IND enabling studies and subsequent clinical trials for the GM2 Gangliosidoses.